Promising New Target May Treat Pulmonary Fibrosis

By uncovering the mechanism by which fibrous tissue cells in the lung multiply, researchers have identified a promising new approach for the treatment of pulmonary fibrosis. The research is published in Journal of Pathology.

﻿﻿Idiopathic pulmonary fibrosis or IPF- where the disease appears spontaneously and without a known cause - is a severe, chronic lung disease in which the rapid growth of fibrous tissue results in increasingly severe breathing difficulties and a high mortality rate.

Excessive signaling of the growth factor TGF-β is recognized as a central player in lung fibrosis, and its increased expression has been identified in both IPF patients and experimental models of the disease. However, in addition to its pro-fibrotic effect, TGF-β signaling is essential to aspects of other systems, such as appropriate immune response. Therefore, complete therapeutic blockade of TGF-β pathway isn't ideal, and the researchers' goal was to find a way to target specific cells that result in fibrosis without affecting other cells.

Using a unique transgenic mouse model, the researchers were able to manipulate TGF-β signaling in adult lung mesenchymal cells at selected stages of lung fibrosis. They showed that the progression of fibrosis mediated by TGF-β was independent of early inflammatory processes during initiation of fibrosis - an understanding that is vital in designing therapeutic strategies to stop its progression in IPF patients.

Secondly, they identified a downstream gene called P4HA3 that is important to the overabundant collagen deposition associated with IPF. This gene encodes a component of prolyl 4-hydroxylase, a key enzyme in collagen synthesis. Inhibition of this enzyme was shown to reduce the TGF-β-stimulated collagen production in both cultured fibroblasts (connective tissue cells that produces collagen) and mouse models of lung fibrosis.

The data indicate that increased expression of collagen prolyl hydroxylase is one of the important mechanisms underlying the proliferation of fibrous tissue that is mediated by TGF-β. "Inhibiting this enzyme appears to be a promising therapy to interfere with excessive collagen production and deposition in IPF patients," the researchers concluded.